Neural Stimulation for Reduced Artefact

ABSTRACT

A neural stimulus comprises at least three stimulus components, each comprising at least one of a temporal stimulus phase and a spatial stimulus pole. A first stimulus component delivers a first charge which is unequal to a third charge delivered by a third stimulus component, and the first charge and third charge are selected so as to give rise to reduced artefact at recording electrodes. In turn this may be exploited to independently control a correlation delay of a vector detector and an artefact vector to be non-parallel or orthogonal.

CROSS-REFERENCE TO RELATED APPLICATIONS

The current application is a continuation of U.S. patent applicationSer. No. 16/311,526 filed Dec. 19, 2018, which is a national stage ofPCT Application No. PCT/AU2017/050647 filed Jun. 23, 2017, which claimsthe benefit of Australian Provisional Patent Application No. 2016902492filed Jun. 24, 2016, the disclosures of which are hereby incorporated byreference in their entireties.

TECHNICAL FIELD

The present invention relates to neural stimulation, and in particularto a method and device configured to deliver a neural stimulus in amanner to give rise to reduced amounts of artefact so as to ease thetask of recording a neural response evoked by the neural stimulus.

BACKGROUND OF THE INVENTION

Electrical neuromodulation is used or envisaged for use to treat avariety of disorders including chronic pain, Parkinson's disease, andmigraine, and to restore function such as hearing and motor function. Aneuromodulation system applies an electrical pulse to neural tissue inorder to generate a therapeutic effect. Such a system typicallycomprises an implanted electrical pulse generator, and a power sourcesuch as a battery that may be rechargeable by transcutaneous inductivetransfer. An electrode array is connected to the pulse generator, and ispositioned close to the neural pathway(s) of interest. An electricalpulse applied to the neural tissue by an electrode causes thedepolarisation of neurons, which generates propagating action potentialswhether antidromic, orthodromic, or both, to achieve the therapeuticeffect.

When used to relieve chronic pain for example, the electrical pulse isapplied to the dorsal column (DC) of the spinal cord and the electrodearray is positioned in the dorsal epidural space. The dorsal columnfibres being stimulated in this way inhibit the transmission of painfrom that segment in the spinal cord to the brain.

In general, the electrical stimulus generated in a neuromodulationsystem triggers a neural action potential which then has either aninhibitory or excitatory effect. Inhibitory effects can be used tomodulate an undesired process such as the transmission of pain, orexcitatory effects can be used to cause a desired effect such as thecontraction of a muscle or stimulation of the auditory nerve.

The action potentials generated among a large number of fibres sum toform a compound action potential (CAP). The CAP is the sum of responsesfrom a large number of single fibre action potentials. When a CAP iselectrically recorded, the measurement comprises the result of a largenumber of different fibres depolarising. The propagation velocity isdetermined largely by the fibre diameter and for large myelinated fibresas found in the dorsal root entry zone (DREZ) and nearby dorsal columnthe velocity can be over 60 ms⁻¹. The CAP generated from the firing of agroup of similar fibres is measured as a positive peak P1 in therecorded potential, then a negative peak N1, followed by a secondpositive peak P2. This is caused by the region of activation passing therecording electrode as the action potentials propagate along theindividual fibres, producing the typical three-peaked response profile.Depending on stimulus polarity and the sense electrode configuration,the measured profile of some CAPs may be of reversed polarity, with twonegative peaks and one positive peak.

Approaches proposed for obtaining a neural measurement are described bythe present applicant in International Patent Publication No. WO2012/155183, the content of which is incorporated herein by reference.

To better understand the effects of neuromodulation and/or other neuralstimuli, and for example to provide a stimulator controlled by neuralresponse feedback, it is desirable to accurately detect and record a CAPresulting from the stimulus. Evoked responses are less difficult todetect when they appear later in time than the artefact, or when thesignal-to-noise ratio is sufficiently high. The artefact is oftenrestricted to a time of 1-2 ms after the stimulus and so, provided theneural response is detected after this time window, a responsemeasurement can be more easily obtained. This is the case in surgicalmonitoring where there are large distances (e.g. more than 12 cm fornerves conducting at 60 ms⁻¹) between the stimulating and recordingelectrodes so that the propagation time from the stimulus site to therecording electrodes exceeds 2 ms.

However to characterize the responses from the dorsal columns, highstimulation currents and close proximity between electrodes arerequired. Similarly, any implanted neuromodulation device willnecessarily be of compact size, so that for such devices to monitor theeffect of applied stimuli the stimulus electrode(s) and recordingelectrode(s) will necessarily be in close proximity. In such situationsthe measurement process must overcome artefact directly. However, thiscan be a difficult task as an observed CAP signal component in theneural measurement will typically have a maximum amplitude in the rangeof microvolts. In contrast a stimulus applied to evoke the CAP istypically several volts and results in electrode artefact, whichmanifests in the neural measurement as a decaying output of severalmillivolts partly or wholly contemporaneously with the CAP signal,presenting a significant obstacle to isolating or even detecting themuch smaller CAP signal of interest.

For example, to resolve a 10 μV CAP with 1 μV resolution in the presenceof an input 5 V stimulus, for example, requires an amplifier with adynamic range of 134 dB, which is impractical in implant systems. As theneural response can be contemporaneous with the stimulus and/or thestimulus artefact, CAP measurements present a difficult challenge ofmeasurement amplifier design. In practice, many non-ideal aspects of acircuit lead to artefact, and as these mostly have a decayingexponential appearance that can be of positive or negative polarity,their identification and elimination can be laborious.

The difficulty of this problem is further exacerbated when attempting toimplement CAP detection in an implanted device. Typical implants have apower budget which permits a limited number, for example in the hundredsor low thousands, of processor instructions per stimulus, in order tomaintain a desired battery lifetime. Accordingly, if a CAP detector foran implanted device is to be used regularly (e.g. once a second), thencare must be taken that the detector should consume only a smallfraction of the power budget.

Daly (U.S. Pat. No. 8,454,529) suggests application of a stimulus,followed by a compensatory pulse, however Daly's biphasic stimulus andcompensatory pulse together are not charge balanced and thus cause a netcharge transfer between the device and the tissue.

Any discussion of documents, acts, materials, devices, articles or thelike which has been included in the present specification is solely forthe purpose of providing a context for the present invention. It is notto be taken as an admission that any or all of these matters form partof the prior art base or were common general knowledge in the fieldrelevant to the present invention as it existed before the priority dateof each claim of this application.

Throughout this specification the word “comprise”, or variations such as“comprises” or “comprising”, will be understood to imply the inclusionof a stated element, integer or step, or group of elements, integers orsteps, but not the exclusion of any other element, integer or step, orgroup of elements, integers or steps.

In this specification, a statement that an element may be “at least oneof” a list of options is to be understood that the element may be anyone of the listed options, or may be any combination of two or more ofthe listed options.

SUMMARY OF THE INVENTION

According to a first aspect, the present invention provides a method ofevoking and detecting a neural response, the method comprising:

-   -   applying a stimulus to evoke a neural response, the stimulus        comprising at least three stimulus components, each stimulus        component comprising at least one of a temporal stimulus phase        and a spatial stimulus pole, wherein a first stimulus component        delivers a first charge which is unequal to a third charge        delivered by a third stimulus component, the first charge and        third charge being selected so as to give rise to reduced        artefact at recording electrodes;    -   using the recording electrodes to obtain a recording of the        neural response; and    -   detecting the neural response in the recording with a vector        detector;    -   wherein a correlation delay of the vector detector, and the        first charge and third charge of the stimulus, have values which        cause a produced artefact vector to be non-parallel to an evoked        neural response vector.

According to a second aspect the present invention provides animplantable device for delivering a neural stimulus, the devicecomprising:

-   -   an array of electrodes comprising at least one nominal stimulus        electrode and at least one nominal recording electrode; and    -   a processor configured to cause the at least one nominal        stimulus electrode to apply a stimulus to evoke a neural        response, the stimulus comprising at least three stimulus        components, each stimulus component comprising at least one of a        temporal stimulus phase and a spatial stimulus pole, wherein a        first stimulus component delivers a first charge which is        unequal to a third charge delivered by a third stimulus        component, the first charge and third charge being selected so        as to give rise to reduced artefact at recording electrodes, the        processor further configured to cause the at least one nominal        recording electrode to obtain a recording of the neural        response, the processor further configured to detect the neural        response in the recording with a vector detector;    -   wherein a correlation delay of the vector detector, and the        first charge and third charge of the stimulus, have values which        cause a produced artefact vector to be non-parallel to an evoked        neural response vector.

According to a third aspect the present invention provides anon-transitory computer readable medium for delivering a neuralstimulus, comprising instructions which, when executed by one or moreprocessors, causes performance of the following:

-   -   applying a stimulus to evoke a neural response, the stimulus        comprising at least three stimulus components, each stimulus        component comprising at least one of a temporal stimulus phase        and a spatial stimulus pole, wherein a first stimulus component        delivers a first charge which is unequal to a third charge        delivered by a third stimulus component, the first charge and        third charge being selected so as to give rise to reduced        artefact at recording electrodes;    -   using the recording electrodes to obtain a recording of the        neural response; and    -   detecting the neural response in the recording with a vector        detector;    -   wherein a correlation delay of the vector detector, and the        first charge and third charge of the stimulus, have values which        cause a produced artefact vector to be non-parallel to an evoked        neural response vector.

The first to third aspects of the invention recognise that suitableadjustments to or selection of the inequality or duty ratio between thefirst charge and third charge can cause an artefact vector to benon-parallel to, and more preferably substantially orthogonal to, anevoked neural response vector, so that a contribution of artefact to theoutput of the vector detector passes a zero, thereby considerablyimproving observation of the evoked neural response.

Some embodiments of the invention may utilise static predefined valuesfor the inequality or duty ratio between the first charge and thirdcharge and for the correlation delay of the vector detector. However,other embodiments may adaptively adjust the stimulus duty ratio and/orcorrelation delay in order to seek out a zero in the artefactcontribution. Such adaptive embodiments provide a means by which torepeatedly or continually optimise the reduction of artefact observed inthe recording.

In embodiments where the stimulus components comprise stimulus phasesand the stimulus is a triphasic stimulus, the first charge preferablyexceeds the third charge. In such embodiments the first charge ispreferably between 0.51 and 0.99 times the magnitude of the secondcharge, more preferably between 0.6 and 0.9 times the magnitude of thesecond charge, more preferably between 0.65 and 0.8 times the magnitudeof the second charge, and most preferably about 0.75 times the magnitudeof the second charge.

Embodiments of the first to third aspects may utilise any suitablevector detector. The vector detector may for example utilise afour-lobed or five-lobed matched filter template in accordance with theteachings of the present applicant's International Patent PublicationNo. WO2015074121, the content of which is incorporated herein byreference. Alternatively, the detector which produces a signed outputmay utilise an alternative matched filter template such as a two-lobedor three-lobed matched filter template, the lobes being sinusoidal ormatched to two or three lobes of a synthesised or actual measuredcompound action potential profile or otherwise suitably shaped.

Some embodiments of the invention recognise that while adjusting a delayT in the detector correlation permits the evoked response vector to bedesirably aligned (as described in relation to FIG. 7 of WO2015074121for example), separately adjusting the inequality or duty ratio betweenthe first and third phase of a triphasic stimulus permits independentcontrol over the artefact vector, so that the artefact vector may becontrolled to occur non-parallel to the evoked response vector, and morepreferably so that the artefact vector is controlled to occur largely orsubstantially orthogonal to the evoked response vector.

In some embodiments the at least three stimulus components are temporalstimulus phases of a bipolar stimulus delivered by two stimuluselectrodes. Additionally or alternatively, the at least three stimuluscomponents may comprise spatial stimulus poles of a biphasic tripolarstimulus delivered by three stimulus electrodes, each stimulus poledefined herein as representing the charge transfer between therespective stimulus electrode and the surrounding tissue.

In some embodiments of the first to third aspects of the invention, thestimulus might not be charge balanced, and the net charge difference canbe recovered by alternative means such as passively recovering charge byshorting one or more electrodes to ground at appropriate times.

According to a fourth aspect the present invention provides a method ofdelivering a neural stimulus, the method comprising:

-   -   delivering a first stimulus phase and a third stimulus phase        which are of a first polarity;    -   delivering a second stimulus phase which is of a second polarity        opposite the first polarity, after the first stimulus phase and        prior to the third stimulus phase;    -   wherein the first to third phases are charge balanced, and        wherein the first stimulus phase delivers a first charge which        is unequal to a third charge delivered by the third stimulus        phase, the first charge and third charge being selected so as to        give rise to reduced artefact.

According to a fifth aspect the present invention provides animplantable device for delivering a neural stimulus, the devicecomprising:

-   -   an array of electrodes comprising at least one nominal stimulus        electrode and at least one nominal sense electrode; and    -   a processor configured to cause the at least one nominal        stimulus electrode to deliver a first stimulus phase and a third        stimulus phase which are of a first polarity, and to deliver a        second stimulus phase which is of a second polarity opposite the        first polarity and which is delivered after the first stimulus        phase and prior to the third stimulus phase, wherein the first        to third phases are charge balanced, and wherein the first        stimulus phase delivers a first charge which is unequal to a        third charge delivered by the third stimulus phase, the first        charge and third charge being selected so as to give rise to        reduced artefact at the at least one nominal sense electrode.

According to a sixth aspect the present invention provides anon-transitory computer readable medium for delivering a neuralstimulus, comprising instructions which, when executed by one or moreprocessors, causes performance of the following:

-   -   delivering a first stimulus phase and a third stimulus phase        which are of a first polarity;    -   delivering a second stimulus phase which is of a second polarity        opposite the first polarity, after the first stimulus phase and        prior to the third stimulus phase;    -   wherein the first to third phases are charge balanced, and        wherein the first stimulus phase delivers a first charge which        is unequal to a third charge delivered by the third stimulus        phase, the first charge and third charge being selected so as to        give rise to reduced artefact.

The first charge may be made unequal to the third charge by causing thefirst and third stimulus phases to have unequal current amplitude,and/or unequal duration, and/or unequal morphology.

In embodiments of the fourth to sixth aspects of the invention apeak-to-peak detector may be used to process the recording. While apeak-to-peak detector does not go through a zero irrespective of theduty ratio between the first charge and third charge, suitableadjustments of the duty ratio between the first charge and third chargenevertheless permit a minima in the detector output to be sought thusproviding a means by which to give rise to reduced artefact in therecording.

In alternative embodiments the described stimulus of the first throughsixth aspects may be delivered in the absence of any related ECAPrecording, for example in order to preserve desirable electrical tissueconditions until such time as an ECAP measurement might later bedesired.

BRIEF DESCRIPTION OF THE DRAWINGS

An example of the invention will now be described with reference to theaccompanying drawings, in which:

FIG. 1 schematically illustrates an implanted spinal cord stimulator;

FIG. 2 is a block diagram of the implanted neurostimulator;

FIG. 3 is a schematic illustrating interaction of the implantedstimulator with a nerve;

FIG. 4 illustrates the current profile of a triphasic stimulus, havingunequal phase durations, in accordance with some embodiments of theinvention;

FIG. 5 schematically illustrates delivery of a stimulus to neuraltissue;

FIGS. 6 and 7 illustrate the effect of varying a detector time delay anda triphasic stimulus duty ratio;

FIG. 8 illustrates the results of experimental testing of variabletriphasic duty ratio;

FIG. 9 shows the peak-to-peak artefact for tri-phasic stimulation;

FIGS. 10a, 10b, 11a, and 11b illustrate the improved reduced artefactarising in human subject tests;

FIG. 12 illustrates a conceptualisation of some embodiments of theinvention having unequal phase durations;

FIG. 13 illustrates the current profile of a triphasic stimulus, havingunequal phase amplitudes, in accordance with other embodiments of theinvention

FIGS. 14a and 14b illustrate the spatial electrode configuration, andthe tripolar stimulus, respectively, in accordance with anotherembodiment of the invention;

FIG. 15 illustrates derivation of, and the final form of, a quadraphasicstimulus in accordance with another embodiment of the invention; and

FIG. 16 illustrates a process for optimising a stimulation waveformand/or configuration in order to minimise artefact.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

FIG. 1 schematically illustrates an implanted spinal cord stimulator100. Stimulator 100 comprises an electronics module 110 implanted at asuitable location in the patient's lower abdominal area or posteriorsuperior gluteal region, and an electrode assembly 150 implanted withinthe epidural space and connected to the module 110 by a suitable lead.Numerous aspects of operation of implanted neural device 100 arereconfigurable by an external control device 192. Moreover, implantedneural device 100 serves a data gathering role, with gathered data beingcommunicated to external device 192.

FIG. 2 is a block diagram of the implanted neurostimulator 100. Module110 contains a battery 112 and a telemetry module 114. In embodiments ofthe present invention, any suitable type of transcutaneous communication190, such as infrared (IR), electromagnetic, capacitive and inductivetransfer, may be used by telemetry module 114 to transfer power and/ordata between an external device 192 and the electronics module 110.

Module controller 116 has an associated memory 118 storing patientsettings 120, control programs 122 and the like. Controller 116 controlsa pulse generator 124 to generate stimuli in the form of current pulsesin accordance with the patient settings 120 and control programs 122.Electrode selection module 126 switches the generated pulses to theappropriate electrode(s) of electrode array 150, for delivery of thecurrent pulse to the tissue surrounding the selected electrode(s).Measurement circuitry 128 is configured to capture measurements ofneural responses sensed at sense electrode(s) of the electrode array asselected by electrode selection module 126.

FIG. 3 is a schematic illustrating interaction of the implantedstimulator 100 with a nerve 180, in this case the spinal cord howeveralternative embodiments may be positioned adjacent any desired neuraltissue including a peripheral nerve, visceral nerve, parasympatheticnerve or a brain structure. Electrode selection module 126 selects astimulation electrode 2 of electrode array 150 to deliver a triphasicelectrical current pulse to surrounding tissue including nerve 180,although other embodiments may additionally or alternatively deliver abiphasic tripolar stimulus. Electrode selection module 126 also selectsa return electrode 4 of the array 150 for stimulus current recovery tomaintain a zero net charge transfer.

Delivery of an appropriate stimulus to the nerve 180 evokes a neuralresponse comprising a compound action potential which will propagatealong the nerve 180 as illustrated, for therapeutic purposes which inthe case of a spinal cord stimulator for chronic pain might be to createparaesthesia at a desired location. To this end the stimulus electrodesare used to deliver stimuli at 30 Hz. To fit the device, a clinicianapplies stimuli which produce a sensation that is experienced by theuser as a paraesthesia. When the paraesthesia is in a location and of asize which is congruent with the area of the user's body affected bypain, the clinician nominates that configuration for ongoing use.

The device 100 is further configured to sense the existence andelectrical profile of compound action potentials (CAPs) propagatingalong nerve 180, whether such CAPs are evoked by the stimulus fromelectrodes 2 and 4, or otherwise evoked. To this end, any electrodes ofthe array 150 may be selected by the electrode selection module 126 toserve as measurement electrode 6 and measurement reference electrode 8.The stimulator case may also be used as a measurement or referenceelectrode, or a stimulation electrode. Signals sensed by the measurementelectrodes 6 and 8 are passed to measurement circuitry 128, which forexample may operate in accordance with the teachings of InternationalPatent Application Publication No. WO2012155183 by the presentapplicant, the content of which is incorporated herein by reference. Thepresent invention recognises that in circumstances such as shown in FIG.3 where the recording electrodes are close to the site of stimulation,stimulus artefact presents a significant obstacle to obtaining accuraterecordings of compound action potentials, but that reliable accurate CAPrecordings are a key enabler for a range of neuromodulation techniques.

To this end the present embodiment of the present invention provides fordelivering such neural stimulation in a manner which gives rise toreduced artefact, the method being based on triphasic and/or tripolarstimulus waveforms. FIG. 4 illustrates the general current profile of asuitable triphasic stimulus 400 for implementing the present inventionin some embodiments of the invention. The stimulus 400 delivers apositive charge transfer of Q1 and Q3 in the first and third phasesrespectively. A negative charge transfer of Q2 is delivered in thesecond phase. In accordance with the present invention the stimulus 400is charge balanced, so that |Q2|=Q1+Q3. In accordance with the presentinvention Q1≠Q3, with the respective values of Q1 and Q3 being selectedin a manner which minimises artefact. This is achieved by delivering allthree phases at the same magnitude I, but for differing durations. Inthis embodiment the duration of the first phase is 0.75 times theduration of the second phase, so that Q1=0.75Q2. The duration of thethird phase is 0.25 times the duration of the second phase, so thatQ3=0.25Q2. The inventors have determined that a first phase to thirdphase charge ratio of 0.75:0.25 proves to be a particularly robustsetting for Q1 and Q3, even between different devices and differenthuman subjects. However the duty ratio of the first and third phases canbe adjusted by considering a parameter 0<α<1 (α≠0.5), or in preferredembodiments 0.5<α<1, whereby in accordance with the present inventionQ1=α Q2, and Q3=(1-α) Q2. The interphase gaps of stimulus 400 each maybe adjusted in duration or may be omitted.

FIG. 5 schematically illustrates delivery of the stimulus 400 to theneural tissue. In a first embodiment, neural response signals observedby electrodes 6 and 8 are processed by the controller 116 using adot-product detector, in the manner disclosed in the present applicant'sInternational Patent Publication No. WO2015074121, the content of whichis incorporated herein by reference. Beneficially, such embodimentsrecognise that a dot product detector produces an output that can bepositive or negative depending in the relative phase of the artefact andthe detector. As shown in FIGS. 6 and 7, and described more fully inWO2015074121 in relation to FIG. 7 of that publication in particular,varying a detector time delay τ influences a phase angle of the observedneural response vector. The present invention further recognises thatvarying the duty ratio a of stimulus 400 influences the phase angle ofthe artefact as measured by the detector output. The parameters τ and athus provide independent control over neural response vector phase angleand artefact vector phase angle, permitting orthogonal positioning ofthe two vectors to be sought as shown in FIG. 7.

FIG. 8 illustrates the results of experimental testing of variabletriphasic duty ratio in a human subject, as observed on four differentelectrodes of the array. The parameter α was varied from 0.1 to 0.9(shown as percentages on the x-axis in FIG. 8), the resulting triphasicstimulus was delivered, and the observed neural response on each of thefour electrodes was processed by a dot product detector as described inWO2015074121. The output of the dot product detector is plotted in FIG.8. It is noted that the measure of artefact produced by using a dotproduct detector consists of the peak-to-peak value of the equivalentECAP that would produce the same output. FIG. 8 reveals that if 70% ofthe positive stimulation is in the first phase (i.e., if α=0.7), theartefact is approximately zero, for all electrodes. Moreover, thisresult has shown itself to be quite robust against variation in leadtype, and other stimulation parameters. Alternative embodiments may ofcourse select a different value of a as appropriate to compensate fordifferent hardware or firmware settings or if required between patients.

In a second embodiment, the neural response signals observed byelectrodes 6 and 8 are processed by the controller 116 usingpeak-to-peak detection. A peak-to-peak detector can only produce apositive value for the artefact. FIG. 9 shows the peak-to-peak artefactfor tri-phasic stimulation as a function of the ratio of the first andthird pulses. Again, observations were made for four different senseelectrodes of the array to produce the four traces of FIG. 9.

When compared to a biphasic waveform, which has a 0% duty cycle (α=0),extrapolating the graph of FIG. 9 would be expected to give artefact ofat least 40 μV. Thus, the variable duty-cycle tri-phasic stimulationproduces a trough through the range 0.2<α<0.7), which may be ofassistance in some scenarios. However this trough is only a few dB lowerthan the peak value and so of lesser value than the embodiment of FIG.8.

A further particular advantage of some embodiments of the presentinvention is that the parameter a is orthogonal to other methods ofartefact reduction and thus may be used in conjunction with such othermethods. These other methods include methods based in linearity, such asalternating phase and subtraction.

The alternating phase method of artefact reduction relies on theequation A(I)=−A(−I), where A(I) is the artefact at current I. ThusA(I)+A(−I)=0, so consecutive neural response measurements obtained inresponse to a first stimulus of one phase followed by a stimulus whichis of opposite phase may reduce artefact by subtracting theconsecutively obtained response measurements.

The subtraction method of artefact reduction also relies on linearity.A(I)=2.A(I/2). Thus artefact reduction can also be achieved by obtainingconsecutive neural response measurements in response to a first stimulusof one amplitude and a second stimulus of double the amplitude, andA(I)-2A(I/2)=0.

Linearity methods can provide around 20 dB of artefact rejection. Inconventional neuromodulation biphasic stimulation is often used togenerate evoked responses. It produces artefact having a fixed polaritycompared to the stimulus so inverting the polarity of the stimulusinverts the polarity of the artefact. This leads to alternating phasestimulation where averages across successive stimuli lead tocancellation of artefact voltage but not ECAP. This works, but has itsown problems e.g. reduction in ECAP size, multiple stimulation sitesetc. Or slower effective stimulation rate, meaning higher powerconsumption per therapeutic stimulus.

The method of the present invention may additionally or alternatively becombined with artefact reduction methods which are based on detection,as described in WO2015074121 and utilised in the embodiment of FIGS.6-8. These methods used a four-lobe detector to eliminate the DC, linearand quadratic terms from the artefact's Taylor expansion. Detectionmethods provide around 16 dB of artefact rejection.

The variable triphasic methods described herein when used in combinationwith such other artefact reduction techniques have been shown to providea further 13 dB of artefact rejection. It will be noticed that thesemethods are orthogonal to each other i.e. they can be used inconjunction. It is expected that this will provide 20+16+9 dB=42 dB ofartefact rejection. This can reduce a (typical large) artefact of 500uVobserved in spinal cord stimulation patients to an ECAP equivalent of5uV.

In yet another embodiment, the parameter a may be adaptively validated,and adjusted if required, occasionally or substantially continuouslyover time. In such embodiments, tri-phasic stimulation is delivered athalf the therapeutic current, which allows the system to measure theartefact at the detector output in the absence of any evoked ECAP. Thisallows the system to dynamically adjust the duty cycle to find the nullin artefact, optimized for the specific circumstances. This also allowsopposite phase triphasic stimuli to be delivered beneath the recruitmentthreshold, in order to provide the opposite phase signal forcancellation via the linearity technique.

While the embodiment of FIG. 8 utilised the 4 lobe matched filtertemplate described in WO2015074121, it is to be noted that alternativeembodiments of the present invention may use any suitable dot-productdetector, including 2- and 3-lobe matched filter dot product detectors.Such embodiments may even be preferable in some instances as they can bebetter at rejecting white noise or non-artefact noise than the 4-lobedot product detector.

FIGS. 10-11 illustrate data obtained from a single human subject havinga spinal cord stimulator utilising the embodiment of FIG. 8. In FIG. 10athe artefact observed in obtained neural measurements when the subjectis sitting can be seen to be substantially reduced by the triphasicstimulus in accordance with the present invention, at 6 mA stimuluscurrent. FIG. 10b shows the observed neural response amplitude plottedagainst varying input stimulus current from 0-8 mA, for both triphasic(1002) and biphasic (1004) stimulation for the same human subject. Belowabout 6 mA no compound action potential is being evoked and the observedsignals comprise only artefact, with the results for biphasicstimulation clearly being much worse (larger) then the results foradjusted duty ratio triphasic stimulation in accordance with the presentinvention. Moreover, the stimulus threshold, above which compound actionpotentials are being evoked by the applied stimuli, is a criticalparameter for most neuromodulation applications. The stimulus thresholdis clearly manifested as a kneepoint in the plot 1002 provided by thepresent invention at around 6 mA stimulus current, but is far moredifficult or even impossible to discern in the biphasic results 1004.Additionally, the slope of the growth curve above the stimulusthreshold, another critical parameter in many neuromodulationapplications, is much less affected by noise in the plot 1002 than in1004.

FIGS. 11a and 11b correspond to FIG. 10, for data obtained when thesubject was supine. Again, significant artefact reduction is clearlyprovided by the adjusted duty ratio triphasic stimulation of the presentinvention.

Without intending to be limited by theory, as shown in FIG. 12 triphasicstimulation can be compared to or conceptualised as being two biphasicstimuli in succession. So the artefact should be the electrical sum ofthe artefact of the individual stimuli. Due to the time delay (t₁-t₂)the artefact waveforms do not cancel if they arise from equal biphasicstimuli. The present invention can be thought of as giving the twobi-phasic waveforms unequal pulse widths, and/or unequal amplitudeand/or an inequality of any other suitable characteristic, in a mannerwhich makes the size of the positive and negative artefact contributionsa₁ and a₂ unequal upon creation but with the intention of making themcancel once the time delay (t₁-t₂) provides for some decay of a₁.

The conceptualisation of the variable ratio triphasic stimulus shown inFIG. 12, where the second phase is conceived as two unequal durationphases with no interphase gap, suggests a further suite of embodimentswhich are also within the scope of the invention. In such embodiments,an interphase gap is introduced to effectively split the second phaseinto two phases. Such embodiments thus include stimulus waveforms thatcomprise more than three phases. In the case of a four phase stimulusthe charge delivered by each phase in such embodiments could for examplebe configured to be α, −α,−(1−α), +(1−α), respectively, as isimmediately suggested by FIG. 12. However, the use of four phasespermits other variations in the charges delivered by each phase, so thatmore generally the charges delivered by each phase could comprise +X μC,−Y μC, −Z μC, and +(Y+Z−X) μC, respectively, with each phase beingtemporally separated from the adjacent phase by brief interphase gapseach being of any suitable value, and such embodiments are within thepresent invention provided that the values of a, X, Y and Z are selectedso as to accomplish the required charge balancing and reduction inartefact experienced by the recording electrodes.

Considering yet another embodiment, shown in FIG. 13, it is noted thatadjusting the amplitude of the waveform, but not the pulse width, alsoprovides for a suitable triphasic waveform to be produced. The stimuluswaveform of FIG. 13 can, similarly to FIG. 12, be seen as the sum of twobiphasic waveforms that will have opposite artefact. By adjusting theamplitudes a and b, while keeping (a+b) at the required charge toachieve a desired therapeutic effect, the artefact terms of the twosub-components will be expected to cancel in the corresponding manner asshown in FIG. 12.

It is to be appreciated that in still other embodiments, the unequalphase amplitude approach of FIG. 13 may be combined with the unequalphase duration amplitude approach of FIGS. 4 and 12.

In still other embodiments, a tripolar stimulus may be applied in themanner shown in FIGS. 14a and 14b . The spatial positioning of theelectrodes, as shown in FIG. 14a , can be exploited by appropriatelyconfigured current pulses as shown in FIG. 14b . The waveforms onelectrode 2 and 3 will have artefact of opposite polarity. Again, byadjusting the amplitudes a and b, while keeping (a+b) at the requiredcharge, the artefact terms of the two sub-components will be expected tocancel spatially at some point, and can be configured to preferentiallycancel artefact at the known nearby location of the recordingelectrodes.

FIG. 15 illustrates application of the principles of the presentinvention in order to yield yet another stimulus waveform in accordancewith another embodiment of the present invention. In this embodiment, aquadraphasic stimulus is formulated from two components; apositive-first biphasic pulse, and a negative-first biphasic pulsecomprising a long interphase gap. The positive-first biphasic pulsecomponent effects the neural stimulus. The negative-first biphasic pulsecomponent provides no stimulation, in that it does not evoke any neuralresponse. The negative-first biphasic pulse does however introduce anartefact, dominated by the second phase, which, when the relativecharges of all four phases are suitably chosen, cancels the artefactarising from the positive-first biphasic component in a correspondingmanner as is shown in FIG. 12.

FIG. 16 illustrates a process 1600 for optimising a stimulation waveformand/or configuration in order to minimise artefact. At 1610 a stimulusis applied, below a threshold for neural recruitment so as to ensurethat neural responses are not evoked and do not contribute tomeasurements. At 1620, artefact resulting from the stimulus is measuredand recorded. At 1640, the ratio between the first and third stimuluscomponents is adjusted, and the steps 1610 and 1620 are repeated as manytimes as desired, in order to explore a desired range of the ratiobetween the first and third stimulus components. For example, the ratiomay be adjusted from 0 to 1 in increments of 0.01. Once step 1630determines that the desired range of ratios between the first and thirdstimulus components has been explored, the process passes on to step1650, where the minima in artefact is identified from all therecordings. The ratio which gave rise to that minimum artefact is thenadopted for ongoing stimulation at supra-threshold therapeutic levels. Asimilar approach may be used to identify optimal ratios of any or allstimulus components, such as the charge delivered by respective phasesand/or by respective electrodes in monopolar, bipolar, tripolar or morethan three pole stimulation configurations, whether deliveringmonophasic, biphasic, triphasic or more than triphasic stimulation,and/or may be used to identify optimal ratios of stimulation phaseamplitudes, stimulation phase widths, and stimulation pulse shapes.Process 1600, or a suitable adaptation thereof, may be executed orcontrolled by device 192 to identify such optimal ratios on a staticbasis, such as once during a post-implantation device programming stage,or only upon occasions of clinical input. Alternatively, process 1600,or a suitable adaptation thereof, may be executed by controller 116 on apreprogrammed or prompted basis, without involvement of device 192 orany clinician, in order to identify such optimal ratios on a dynamic orongoing basis at suitable times throughout operation of the device. Suchsuitable times for execution of process 1600 may be each occasion uponwhich the device 110 detects changed stimulation conditions, such as apostural change of the implant recipient.

The claimed and described electronic functionality can be implemented bydiscrete components mounted on a printed circuit board, or by acombination of integrated circuits, or by an application-specificintegrated circuit (ASIC).

It will be appreciated by persons skilled in the art that numerousvariations and/or modifications may be made to the invention as shown inthe specific embodiments without departing from the spirit or scope ofthe invention as broadly described. For example, while FIG. 4illustrates adjustment of triphasic duty ratio by altering a duration ofthe first and third phases, such adjustments may additionally oralternatively be effected by altering phase current amplitudes.Moreover, the triphasic stimulus may comprise rectangular phases asshown or may comprise phases of sinusoidal, stepped, triangular or anyother suitable profile. While a range of triphasic, tripolar andquadraphasic stimuli have been discussed, it is to be appreciated thatthe described principles of the present invention may be adapted andapplied to formulate stimuli having a larger number of phases or poleswhich nevertheless achieve the aim of reducing artefact and such stimuliare also within the scope of the present invention, and in particularthe first stimulus component as defined herein is to be understood toencompass a stimulus component which temporally arises after othercomponents of a multiphasic stimuli, and the third stimulus component asdefined herein is to be understood to encompass a stimulus componentwhich may arise prior to, be contemporaneous with, or arise after, thefirst stimulus component. Moreover, the first stimulus component and thethird stimulus component as defined herein are further to be understoodto encompass stimulus components which have zero, one, or more otherstimulus components physically or temporally interposed between thefirst stimulus component and the third stimulus component. The presentembodiments are, therefore, to be considered in all respects asillustrative and not limiting or restrictive.

1. A method of delivering a neural stimulus, the method comprising:delivering a first stimulus phase and a third stimulus phase which areof a first polarity; and delivering a second stimulus phase which is ofa second polarity opposite the first polarity, after the first stimulusphase and prior to the third stimulus phase; wherein the first to thirdstimulus phases are charge balanced, and wherein the first stimulusphase has a first pulse width which is unequal to a third pulse width ofthe third stimulus phase, the second stimulus phase has a second pulsewidth, and the first pulse width and the third pulse width beingselected so as to give rise to reduced artefact.
 2. (canceled)
 3. Animplantable device for delivering a neural stimulus, the devicecomprising: an array of electrodes comprising at least one nominalstimulus electrode and at least one nominal sense electrode; and aprocessor configured to cause the at least one nominal stimuluselectrode to deliver a first stimulus phase and a third stimulus phasewhich are of a first polarity, and to deliver a second stimulus phasewhich is of a second polarity opposite the first polarity and which isdelivered after the first stimulus phase and prior to the third stimulusphase, wherein the first to third stimulus phases are charge balanced,and wherein the first stimulus phase has a first pulse width which isunequal to a third charge pulse width of third stimulus phase, thesecond stimulus phase has a second pulse width, and the first pulsewidth and the third pulse width being selected so as to give rise toreduced artefact at the at least one nominal sense electrode.
 4. Anon-transitory computer readable medium for delivering a neuralstimulus, comprising instructions which, when executed by one or moreprocessors, causes performance of the following: delivering a firststimulus phase and a third stimulus phase which are of a first polarity;and delivering a second stimulus phase which is of a second polarityopposite the first polarity, after the first stimulus phase and prior tothe third stimulus phase; wherein the first to third stimulus phases arecharge balanced, and wherein the first stimulus phase has a first pulsewidth which is unequal to a third pulse width of the third stimulusphase, the second stimulus phase has a second pulse width, and the firstpulse width and the third pulse width being selected so as to give riseto reduced artefact.
 5. The method of claim 1, further comprising:obtaining a recording of a response to the neural stimulus; anddetecting a neural response in the recording with a vector detector;wherein the first pulse width and the third pulse width of the neuralstimulus have values that cause an artefact vector produced by thevector detector to be non-parallel to an evoked neural response vectorproduced by the vector detector.
 6. The method of claim 5, wherein theinequality between the first pulse width and the third pulse widthcauses the artefact vector to be substantially orthogonal to the evokedneural response vector.
 7. The method of claim 5, wherein a correlationdelay of the vector detector and a stimulus duty ratio of the firstpulse to the second pulse width of the neural stimulus have values whichcause the artefact vector to be non-parallel to the evoked neuralresponse vector.
 8. The method of claim 7, further comprising adaptivelyadjusting the stimulus duty ratio and/or the correlation delay in orderto seek out a zero in a contribution of artefact to the recording of theneural response.
 9. The method of claim 8, wherein the adjustingcomprises adjusting the correlation delay so as to desirably align theevoked neural response vector.
 10. The method of claim 7, furthercomprising adaptively adjusting a ratio of an amplitude of the firstphase to an amplitude of the second phase in order to seek out a zero ina contribution of artefact to the recording of the neural response. 11.The method of claim 1, wherein the first pulse width is between 0.6times the second pulse width and 0.9 times the second pulse width. 12.The method of claim 11, wherein the first pulse width is 0.75 times thesecond pulse width.
 13. The implantable device of claim 3, furthercomprising: measurement circuitry configured to obtain a recording of aresponse to the neural stimulus; wherein the processor is furtherconfigured to detect a neural response in the recording with a vectordetector; and wherein the first pulse width and the third pulse width ofthe neural stimulus have values that cause an artefact vector producedby the vector detector to be non-parallel to an evoked neural responsevector produced by the vector detector.
 14. The implantable device ofclaim 13, wherein the inequality between the first pulse width and thethird pulse width causes the artefact vector to be substantiallyorthogonal to the evoked neural response vector.
 15. The implantabledevice of claim 13, wherein a correlation delay of the vector detectorand a stimulus duty ratio of the first pulse to the second pulse widthof the neural stimulus have values which cause the artefact vector to benon-parallel to the evoked neural response vector.
 16. The implantabledevice of claim 15, wherein the processor is further configured toadaptively adjust the stimulus duty ratio and/or the correlation delayin order to seek out a zero in a contribution of artefact to therecording of the neural response.
 17. The implantable device of claim16, wherein the adjusting comprises adjusting the correlation delay soas to desirably align the evoked neural response vector.
 18. Theimplantable device of claim 15, wherein the processor is furtherconfigured to adaptively adjust a ratio of an amplitude of the firstphase to an amplitude of the second phase in order to seek out a zero ina contribution of artefact to the recording of the neural response. 19.The implantable device of claim 3, wherein the first pulse width isbetween 0.6 times the second pulse width and 0.9 times the second pulsewidth.
 20. The implantable device of claim 19, wherein the first pulsewidth is 0.75 times the second pulse width.